Cathepsins are a family of lysosomal proteases which include the cysteine protease cathepsins B, H, K, L, O2, and S. These enzymes have a role in processes that involve proteolysis and turnover of specific proteins and tissues in local microenvironments. Cathepsins also initiate proteolytic cascades by proenzyme activation, participate in the expression of functional MHC class II molecules which bind antigenic peptides, and process antigen in antigen-presenting cells. The various members of this family are differentially expressed, and cathepsin L is closely associated with monocytes, macrophages, and other cells of the immune system. The secreted forms of several members of this family function in tissue remodeling through degradation of collagen, laminin, elastin, and other structural proteins and are implicated in inflammation associated with immunological response and in metastasis (Huisman, W. et al. (1974) Biochem. Biophys. Acta 370:297-307; Mizuochi, T. (1994) Immunol. Lett. 43:189-193; and Baldwin, E. T. (1993) Proc. Natl. Acad. Sci. 90:6796-6800).
The various cathepsin proteases differ in their gene structures and in their transcriptional regulation. The cathepsin L gene promoter has no TATA box but includes several SP-1 sites, two AP-2 transcription regulatory element binding sites, and a cAMP response element. Experimental data confirm that expression of cathepsin L is induced by malignant transformation, growth factors, tumor promoters, and cyclic AMP (Troen, B. et al. (1991) Cell Growth Differ. 2:23-31).
Abnormal regulation and expression of cathepsins is evident in various inflammatory disease states. In cells isolated from inflamed synovia, the mRNA for stromelysin, cytokines, TIMP-1, cathepsin, gelatinase, and other molecules is preferentially expressed. Expression of cathepsins L and D is elevated in synovial tissues from patients with rheumatoid arthritis and osteoarthritis. Cathepsin L expression may also contribute to the influx of mononuclear cells which exacerbates the destruction of the rheumatoid synovium (Keyszer, G. M. (1995) Arthritis Rheum. 38:976-984).
The cathepsins are implicated in several other immune responses. In a rat model of human glomerular disease, the administration of a specific, irreversible inhibitor of cysteine protease (trans-epoxysuccinyl-L-leucylamido-(3-methyl)butane) significantly reduced proteinuria (Baricos, W. H. (1991) Arch. Biochem. Biophys. 288:468-72). The platelet aggregating cysteine protease implicated in thrombotic thrombocytopenic purpura shows the characteristics of a lysosomal cathepsin (Consonni, R. (1994) Br. J. Hematol. 87:321-324). In addition, the increased expression and differential regulation of the cathepsins is linked to the metastatic potential of a variety of cancers and as such is of therapeutic and prognostic interest (Chambers, A. F. et al. (1993) Crit. Rev. Oncog. 4:95-114).
The discovery of a new human cathepsin and the polynucleotides encoding it satisfies a need in the art by providing compositions which are useful in the diagnosis, prevention and treatment of disorders associated with cell proliferation.